ABSTRACT Smoking is the leading threat to health of patients living with HIV (PLWH). Unfortunately, the evidence-base for tobacco use disorder treatment in PLWH lags behind that of HIV itself. A 2016 Cochrane meta-analysis of data from 12 clinical trials involving 2,087 participants receiving both medications and behavioral support found modest evidence of improved abstinence in the short term (<6 months), but not long-term. A short-coming of these studies is that treatment algorithms did not include plans for non-response, or relapse to smoking. A newer clinical trial design, the Sequential Multiple Assignment Randomized Trial (SMART), includes a dynamic treatment strategy in which pre- specified decision rules guide the ongoing treatment of both responders and non-responders. This approach allows SMART designs to better mirror the management of chronic relapsing conditions, such as tobacco use disorder. We, therefore, propose a two-arm, two-stage randomized trial of 622 adult PLWH who smoke cigarettes and receive care in one of three health systems. At inception, participants will be randomized to either combination nicotine replacement therapy (NRT) (patch and gum or lozenge) or combination NRT+contingency management (CM). At 12 weeks, responders (non-smoking participants confirmed by exhaled carbon monoxide [eCO]) in both arms will receive 12 more weeks of the same treatment. Non-responders (participants with continued smoking by self-report and/or eCO) in both the NRT and NRT+CM arms will be re-randomized to 12 weeks of treatment, either with varenicline (VAR) or varenicline+CM (VAR+CM). The intervention will be delivered by trained clinical pharmacists. The primary outcome will be eCO-confirmed abstinence at 24 weeks post-enrollment. The specific aims of the proposed study are to: (1) study the effectiveness of a dynamic treatment approach to reduce the prevalence of smoking in a cohort of PLWH, and to identify the optimal approach; (2), study the effectiveness of various dynamic regimens on CD4 count, HIV viral suppression, and VACS index (validated measure of morbidity and mortality risk); and (3) grounded in implementation science and using a Hybrid Effectiveness-Implementation Type I design, identify barriers and facilitators to delivering our intervention to inform future implementation. The study team includes individuals with expertise in tobacco use disorder treatment, HIV and addiction in PLWH, clinical trials, CM, implementation science, and SMART designs. Study components are readily scalable and all interventions are richly evidence-based. This proposal offers innovation as the first use of the following in a smoking intervention targeting PLWH: (1) a SMART design with first-line tobacco treatment medications; (2) clinical pharmacists as key interventionists; (3) VACS Index 2.0 as an outcome among a general sample of PLWH who smoke; and (4) implementation-focused process evaluation of tobacco intervention including pharmacists and CM in HIV clinics. This study holds exceptional promise to transform tobacco use disorder treatment in HIV treatment settings nationally.